In vivo measurements of rates of protein synthesis with radiolabeled precursors are problematic because of uncertainties about the relative contribution of unlabeled amino acids derived from protein breakdown to the precursor pool for protein synthesis. The quantitative autoradiographic method for the determination of local rates of cerebral protein synthesis (lCPS) in vivo with a carboxyl-labeled, aliphatic, branched-chain amino acid as tracer takes into account recycling of the unlabeled species of the tracer amino acid. Rates of cerebral protein synthesis in rats have been shown to increase in regenerating nerve nuclei and decrease in most brain regions during postnatal brain development and with senescence. Cocaine treatment changes lCPS in selective brain regions; the direction of the changes depends on the history of treatment. Studies of normal sleep in monkeys indicate that slow wave sleep is linked with increased rates of lCPS in many brain regions. In hibernating ground squirrels, lCPS is profoundly and reversibly reduced throughout the brain. Light thiopental anesthesia in rats results in widespread but very small decreases in rates of cerebral protein synthesis. In general, changes in lCPS may mark brain regions undergoing long-term adjustments in response to a drug, a treatment, or a change in physiological state. We are studying cerebral protein synthesis in a genetic mouse model of phenylketonuria (PKU). It has been proposed that a reduction in the rate of cerebral protein synthesis during development due to competitive inhibition of transport of neutral amino acids at the blood brain by the hyperphenylalaninemia manifest in PKU may be the cause of mental retardation in the human disease. Our results indicate that in the adult PKU mouse on a normal diet recycling of leucine from protein breakdown into the precursor pool for protein synthesis in brain is substantially increased and rates of cerebral protein synthesis are decreased in some brain regions. - Phenylketonuria, brain, protein synthesis, amino acids, pahenu2 mice, quantitative autoradiography